Aims To evaluate the antifungal activity and to analyse the structure-activity relationship of eleven natural phenolic compounds against four Candida species which are resistant to fluconazole. Methods and Results Four different species of Candida isolates were used: Candida albicans, Candida krusei, Candida tropicalis and Candida dubliniensis. The phenolic compound carvacrol showed the highest anti-Candida bioactivity, followed by thymol and isoeugenol. The obtained minimum inhibitory concentration (MIC) values obtained were used in a quantitative structure-activity relationship (QSAR) analysis where the electronic, steric, thermodynamic and topological descriptors served as dependent variables. According to the descriptors obtained in this QSAR study, the antifungal activity of phenols has a first action specific character which is based on their interaction with plasma or mitochondrial membranes. The second action is based on a steric descriptor-the maximal and minimal projection of the area-which could explain the inability of some phenolic compounds to be biotransformed to quinones methylene by Candida species. Conclusions According to the descriptors obtained in this QSAR study, the anti-Candida activity of ortho-substituted phenols is due to more than one action mechanism. The anti-Candida activity of phenolic compounds can be predicted by their molecular properties and structural characteristics. Significance and Impact of the Study These results could be employed to predict the anti-Candida activity of new phenolic compounds in the search for new alternatives or complementary therapies to combat against candidiasis.